1. Field of the Invention
This invention concerns a diagnostic method for distinguishing between a carcinomatous or precarcinomatous colo-rectal disease and a histologically similar disease which is not carcinomatous or precarcinomatous. This method employs a monoclonal antibody, preferably the antibody IBD-12, which recognizes blood group substance H, an antigen associated with dysplasia in adenomatous colo-rectal polyps.
2. State of the Art
Ulcerative colitis is a chronic, idiopathic inflammatory process of the colon which affects about 0.05% of the population of the Northern industrialized world. The disease is characterized by recurrent bouts of diarrhea and rectal bleeding that may require lifelong medical management. More importantly, it is now well recognized that ulcerative colitis is a premalignant condition, and it has been estimated that about 13% of patients with pancolitis will develop carcinomas. About 1% of all new cases of colon cancer in this country arise as a complication of chronic inflammatory bowel disease. Compared to most colonic malignancies, these cancers tend to occur in a younger age group, to be multifocal, and to behave in a more aggressive fashion.
It is believed that the majority of malignancies in ulcerative colitis can be prevented, because the epithelium of the affected colon undergoes premalignant dysplastic changes prior to the development or carcinoma and these premalignant changes can be detected by regular surveillance biopsies. Since the risk of malignancy increases with duration of disease, being about 5% at 15 years and increasing by 20% with each subsequent decade, yearly colonoscopy and surveillance biopsies are recommended for every patient with ulcerative colitis beginning at 7 to 10 years after diagnosis.
Although seemingly straightforward in theory, the implementation of surveillance has been frought with problems. Six or seven random biopsies from different regions of the colon are usually taken at each colonoscopy. Dysplasia cannot be recognized with the naked eye. Thus, directed biopsy is precluded, and sampling error is a major limitation to the efficacy of the procedure. The biopsy specimens themselves are, in turn, difficult for pathologists to interpret due to the atypical cytologic changes produced by acute inflammation or epithelial regeneration (healing) that resemble dysplasia. Interobserver variation in interpretation of surveillance biopsies varies by 4 to 8% among experienced pathologists and is undoubtedly much higher among nonexpert pathologists. These problems will be greatly alleviated or even eliminated if dysplasia can be recognized both grossly and microscopically.
There are a number of publications concerning ulcerative colitis and carbohydrate expression. However, none of these is directly related to the detection of H substance except Sheahan, Front. gastrointest. Res. Vol. 4, pages 51 to 64 (Karger, Basel 1979). The chemical moiety which defines blood group substance H is an oligosaccharide containing a non-reducing terminal .alpha.-L-fucose linked .beta. 1-3 to galactose which in turn is linked .beta. 13/4 to N-acetylglucosamine. The Sheahan article, "Blood Group ABH Isoantigens in Colonic Mucosa of Patients with Inflammatory Bowel Disease", used the lectin, Ulex europaeus, to determine the presence of H substance. Lectins suffer from the drawbacks listed in Compton et al., Cancer 59: 118 to 127 (1987). In particular, Ulex europaeus lectin is inherently less specific than the IBD-12 monoclonal antibody for substance H because the lectin's specificity resides solely in its reactivity with L-fucose residues regardless of what the fucose is attached to, whereas the IBD-12 recognizes the fucose residue only in the context of sugar moieties which are part of blood group substance H.